Asymmetric Carbon-carbon Research Articles

Enantioselective Seleno‐Michael Addition Reactions Catalyzed by a Chiral Bifunctional N‐Heterocyclic Carbene with Noncovalent Activation

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β-stereogenic center. Despite its success in the formation of various asymmetric carbon-carbon and carbon-heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron-deficient double bond asymmetrically. A chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral β-seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

Fast multipoint immobilization of lipase through chiral L-proline on a MOF as a chiral bioreactor.

In this paper, we describe the facile preparation of a chiral catalyst by the combination of the amino acid, l-proline (Pro), and the enzyme, porcine pancreas lipase (PPL), immobilized on a microporous metal-organic framework (PPL-Pro@MOF). The multipoint immobilization of PPL onto the MOF is made possible with the aid of Pro, which also provided a chiral environment for enhanced enantioselectivity. The application of the microporous MOF is pivotal in maintaining the catalytic activity of PPL, wherein it prevented the leaching of Pro during the catalytic reaction, leading to the enhanced activity of PPL. The prepared biocatalyst was applied in asymmetric carbon-carbon bond formation, demonstrating the potential of this simple approach for chemical transformations.

Enantioselective Carbon-Carbon Bond Cleavage for Biaryl Atropisomers Synthesis

Summary Development of new synthetic strategies for enantioselective carbon-carbon and carbon-heteroatom bond formation is one of the pillars of modern organic chemistry. Whereas significant advances have been achieved in center chirality construction, catalytically asymmetric construction of axial chirality is still under development. Moreover, axially chiral molecules constructed through carbon-carbon and carbon-heteroatom bond cleavage are extremely limited. Here, we report an asymmetric synthesis of biaryl atropisomers via palladium-catalyzed chemoselective carbon-carbon cleavage of 9-aryl-9H-fluoren-9-ols. The reaction demonstrated broad substrate scope and produced the atropisomers in high yields and enantioselectivity. The ring-opening reactivity was considerably accelerated by the torsional strain created by the steric repulsion between two ortho-substituents of the biaryl skeleton in the substrates. The high enantiocontrol hinges on the evolvement of a new TADDOL-based phosphoramidite as ligand. These findings set up a new platform for the development of novel synthetic methods via asymmetric carbon-carbon cleavage.

A sustainable approach to produce activated carbons from pecan nutshell waste for environmentally friendly supercapacitors

Activated carbons are key electrode materials for supercapacitors (SCs) widely used in commercial devices. Here we investigate the preparation of activated solar carbons (ASCs) from pecan nutshell waste for their use as electrode materials for SCs. The ASCs are prepared using a sustainable process where concentrated solar energy is used as heat source for the one-step carbonization/chemical activation using H3PO4. From physical characterization we observed that our prepared ASCs are amorphous carbons, which have well-developed microporous surface of different features related with a pretreatment of pecan nutshell. The ASCs are electrochemically evaluated by cyclic voltammetry in four aqueous electrolytes using a three-electrode system, obtaining capacitances at 5 mVs−1 of 150 and 129 Fg-1 in acidic (0.5 M H2SO4) and environmentally-friendly neutral (1 M CH3COONa) electrolytes, respectively. Finally, we assembled asymmetric carbon-carbon SC cells showing excellent performance compared to a commercial activated carbon, with capacitances around 30 Fg-1 at 0.5 A g−1 with only ∼10% of capacitance loss after 5000 cycles, reveling a high stability, and a widest voltage window with the 1 M CH3COONa electrolyte. Our study provides a novel sustainable approach to use agricultural waste biomass to produce useful electrode materials for energy storage devices using concentrated solar energy.

S-5 触媒的不斉炭素-炭素結合を機軸とする天然物の全合成(記念講演要旨)

S-5 触媒的不斉炭素-炭素結合を機軸とする天然物の全合成(記念講演要旨)

Chiral Bidentate NHC Ligands Based on the 1,1'-Binaphthyl Scaffold: Synthesis and Application in Transition-Metal-Catalyzed Asymmetric Reactions.

The use of the chiral 1,1'-binaphthyl scaffold to construct chiral ligands can be traced back for a long time. However, the development of bidentate NHC ligands based on the same backbone has only appeared recently. In this account, we describe the design and synthesis of a new family of chiral NHC ligands based on the 1,1'-binaphthyl scaffold and demonstrate the applications of these chiral NHC-metal complexes in the catalyzed oxidative kinetic resolution of secondary alcohols, asymmetric carbon-carbon bond formations, hydrosilylations, and cyclizations of 1,6-enynes. The chiral NHC ligands containing the 1,1'-binaphthyl backbone can be synthesized in good yields from enantiomerically pure 1,1'-binaphthyl-2,2'-diamine. These transition metals coordinated with chiral bidentate NHC ligands exhibit high catalytic activities and good enantioselectivities for a wide range of metal-catalyzed asymmetric reactions.

Threonine aldolases: perspectives in engineering and screening the enzymes with enhanced substrate and stereo specificities.

Threonine aldolases have emerged as a powerful tool for asymmetric carbon-carbon bond formation. These enzymes catalyse the unnatural aldol condensation of different aldehydes and glycine to produce highly valuable β-hydroxy-α-amino acids with complete stereocontrol at the α-carbon and moderate specificity at the β-carbon. A range of microbial threonine aldolases has been recently recombinantly produced by several groups and their biochemical properties were characterized. Numerous studies have been conducted to improve the reaction protocols to enable higher conversions and investigate the substrate scope of enzymes. However, the application of threonine aldolases in organic synthesis is still limited due to often moderate yields and low diastereoselectivities obtained in the aldol reaction. This review briefly summarizes the screening techniques recently applied to discover novel threonine aldolases as well as enzyme engineering and mutagenesis studies which were accomplished to improve the catalytic activity and substrate specificity. Additionally, the results from new investigations on threonine aldolases including crystal structure determinations and structural-functional characterization are reviewed.

Creation of chiral materials: Yesterday, today and tomorrow

Chirality is a fundamental characteristic of nature and pervades the world. The chiral materials closely related to our life, especially our health. The thalidomide tragedy, lessons for drug safety and regulation from the late 1950s and the early 1960s, indicated the importance of creating chiral materials in optically pure form. Pasteur was the first to conduct chiral resolution for the preparation of optically active molecules before 1860. Since then, scientists including chemists started to search methods for creating chiral materials like enzyme. After more than one hundred years of efforts, chemists find that the synthetic chiral catalysts (also known as artificial enzymes) catalyzed asymmetric reactions is the door to creating chiral materials. From 1970 to 2001, many efficient and selective catalytic asymmetric reactions and methods have been developed for creating chiral materials. In particular, the successes of catalytic asymmetric hydrogenations and catalytic asymmetric epoxidations and their applications in industrial preparation of chiral drugs enable this research field to won the Nobel Prize for chemistry in 2001. To date, tremendous amount of chiral materials such as chiral pharmaceuticals, chiral agrochemicals, chiral liquid crystals were created in a high selective and efficient manner. We now can create chiral materials like enzymes by using asymmetric catalysis with artificial enzymes as catalysts. The Chinese chemists also made great contributions for creating chiral materials, especially in the past two decades. They developed a series of highly efficient chiral ligands and catalysts including the magical chiral spiro ligands and catalysts, the privileged chiral N , N ￠-dioxides, as well as many original organocatalysts. These catalysts are highly efficient for a wide range of reactions involving asymmetric hydrogenation, asymmetric carbon-carbon bond formations, and asymmetric carbon-heteroatom bond formations, providing chiral alcohols, chiral amines, chiral acids, etc. Many new asymmetric catalytic reactions, new concepts, new strategies were also developed by Chinese chemists, which afforded new methodologies for creating chiral materials. From this century, in order to meet the new demand of mankind on the chiral materials, scientists begin to develop green and sustainable methods for the accurate, powerful and environment-friendly creation of chiral materials. In addition, the creation of chiral materials has been in depth combined with life sciences, environmental sciences, materials science and information sciences, etc. This review focus on the main line of the discovery and development of asymmetric catalysis, in combination with the development in China, to give a brief overview for the journey of creation of chiral materials.

Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation.

The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy--dynamic kinetic asymmetric transformation--involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.

Asymmetric direct vinylogous Michael addition to 2-enoylpyridine N-oxides catalyzed by bifunctional thio-urea.

Catalytic enantioselective direct vinylogous Michael addition of α,α-dicyanoalkenes to 2-enoylpyridine N-oxides with a bifunctional organocatalyst is described. The methodology offers an efficient way to install an asymmetric carbon-carbon bond at the γ-position of α,α-dicyanoalkenes in excellent regio-, diastereo-, and enantioselectivity. Further, application in desymmetrization of achiral α,α-dicyanoalkene to access highly functionalized enantioenriched cyclohexylidenemalononitrile derivatives has been demonstrated.

Asymmetric Stetter reactions catalyzed by thiamine diphosphate-dependent enzymes.

The intermolecular asymmetric Stetter reaction is an almost unexplored transformation for biocatalysts. Previously reported thiamine diphosphate (ThDP)-dependent PigD from Serratia marcescens is the first enzyme identified to catalyze the Stetter reaction of α,β-unsaturated ketones (Michael acceptor substrates) and α-keto acids. PigD is involved in the biosynthesis of the potent cytotoxic agent prodigiosin. Here, we describe the investigation of two new ThDP-dependent enzymes, SeAAS from Saccharopolyspora erythraea and HapD from Hahella chejuensis. Both show a high degree of homology to the amino acid sequence of PigD (39 and 51 %, respectively). The new enzymes were heterologously overproduced in Escherichia coli, and the yield of soluble protein was enhanced by co-expression of the chaperone genes groEL/ES. SeAAS and HapD catalyze intermolecular Stetter reactions in vitro with high enantioselectivity. The enzymes possess a characteristic substrate range with respect to Michael acceptor substrates. This provides support for a new type of ThDP-dependent enzymatic activity, which is abundant in various species and not restricted to prodigiosin biosynthesis in different strains. Moreover, PigD, SeAAS, and HapD are also able to catalyze asymmetric carbon-carbon bond formation reactions of aldehydes and α-keto acids, resulting in 2-hydroxy ketones.

Asymmetric Catalytic Carbon-Carbon Coupling Reactions via Cross-Dehydrogenative Coupling Reactions

Asymmetric catalytic C—C coupling reactions via cross-dehydrogenative coupling are currently among the most attractive and powerful tools in synthetic organic chemistry. In the past few decades, a variety of catalytic asymmetric C—C coupling reactions via cross-dehydrogenative coupling have been reported. Compared with traditional asymmetric C—C bond formation reactions, cross-dehydrogenative coupling strategies have more advantages in terms of power and cost- effective- ness. In this review, the recent studies on enantioselective cross dehydrogenative-coupling are reviewed. Keywords asymmetric catalysis; cross-dehydrogenative coupling; C—H activation

Total Synthesis of Epothilone D: The Nerol/Macroaldolization Approach

A highly convergent and stereocontrolled synthesis of epothilone D (4) is reported. Key features are a cheap and Z-selective synthesis of the northern half based on nerol and acetoacetate and chromium(II)-mediated Reformatsky reactions as a powerful tool for chemoselective asymmetric carbon-carbon bond formations, including an unusual stereospecific macroaldolization.

ChemInform Abstract: Asymmetric Carbon—Carbon Bond Formation under Continuous‐Flow Conditions with Chiral Heterogeneous Catalysts.

AbstractReview: 170 refs.

Asymmetric Carbon–Carbon Bond Formation under Continuous‐Flow Conditions with Chiral Heterogeneous Catalysts

Catalytic asymmetric carbon-carbon bond-forming reactions provide one of the most efficient ways to synthesize optically active compounds, and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover number (TON) is often lower than that of some other reactions, such as asymmetric hydrogenation, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous-flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asymmetric C-C bond-forming reactions under continuous-flow conditions with chiral heterogeneous catalysts.

Cinchona Alkaloid-Catalyzed Stereoselective Carbon-Carbon Bond Forming Reactions

This review provides insights into the patents available on one of the subfields of organocatalytic reactions, specifically, the Cinchona alkaloids-based organocatalytic reactions, involving asymmetric C-C bond construction. Some of the very important achievements in the asymmetric carbon-carbon bond formation by employing the Cinchona alkaloids- based organocatalysts, one of the privileged classes of asymmetric catalysts, have been accentuated. The Cinchona alkaloids-based enantio- and diastereoselective syntheses of a range of amino acid derivatives, bioactive molecules and various synthetic intermediates with high efficiency are also highlighted. Keywords: Asymmetric synthesis, Cinchona alkaloids, C-C bond formation, diastereoselectivity, enantioselectivity, organocatalysis.

ChemInform Abstract: Catalytic Enantioselective Carbon—Carbon Bond Formation Using Cycloisomerization Reactions

AbstractReview: 240 refs.

Catalytic enantioselective carbon-carbon bond formation using cycloisomerization reactions

This review describes important recent advancements in asymmetric cycloisomerization reactions. A wide variety of catalytic and asymmetric strategies have been applied to these reactions over the past twenty years. Cycloisomerization reactions have the ability to produce diverse polycyclic compounds in excellent yields and selectivity. They constitute a powerful and efficient strategy for asymmetric carbon-carbon bond formation in cyclic compounds. Enyne and related olefin cyclizations comprise the majority of reactions of this type and important advances have recently occurred in this area. However, significant changes have also occurred in the area of classical cyclization as well as intramolecular hydroacylation and C–H activation initiated cyclization and these will also be described.

Double Asymmetric Alkylation Reactions Using C2-symmetric Benzene Based Bis(2-amino-2-oxazolines) Chiral Auxiliaries

E-mail: thkim@chonnam.ac.krReceived September 11, 2011, Accepted September 25, 2011Key Words : Chiral auxiliary, Asymmetric alkylation, Bis(2-amino-2-oxazolines)Chiral auxiliary-derived asymmetric alkylations have beenextensively studied and are now important and generalmethods for asymmetric carbon-carbon bond formation.

A toolbox approach for the rapid evaluation of multi-step enzymatic syntheses comprising a ‘mix and match’ E. coli expression system with microscale experimentation

This work describes an experimental ‘toolbox’ for the rapid evaluation and optimisation of multi-step enzymatic syntheses comprising a ‘mix and match’ E. coli-based expression system and automated microwell scale experimentation. The approach is illustrated with a de novo designed pathway for the synthesis of optically pure amino alcohols using the enzymes transketolase (TK) and transaminase (TAm) to catalyze asymmetric carbon-carbon bond formation and selective chiral amine group addition respectively. The E. coli expression system, based on two compatible plasmids, enables pairs of enzymes from previously engineered and cloned TK and TAm libraries to be evaluated for the sequential conversion of different initial substrates. This is complemented by the microwell experimentation which enables efficient investigation of different biocatalyst forms, use of different amine donors and substrate feeding strategies. Using this experimental ‘toolbox’, one-pot syntheses of the diastereoisomers (2S,3S)-2-aminopentane-1,3-diol (APD) and (2S,3R)-2-amino-1,3,4-butanetriol (ABT) were designed and performed, which gave final product yields of 90% mol/mol for APD and 87% mol/mol for ABT (relative to the initial TK substrates) within 25 hours. For the synthesis of APD, the E coli TK mutant D469E was paired with the TAm from Chromobacterium violaceum 2025 while for ABT synthesis the wild-type E. coli TK exhibited the highest specific activity and ee( enantiomeric excess) of >95%. For both reactions, whole-cell forms of the TK-TAm biocatalyst performed better than cell lysates while isopropylamine (IPA) was a preferable amine donor than methylbenzylamine (MBA) since side reactions with the initial TK substrates were avoided. The available libraries of TK and TAm enzymes and scalable nature of the microwell data suggest this ‘toolbox’ provides an efficient approach to early stage bioconversion process design in the chemical and pharmaceutical sectors.